Both the initial susceptibility to addiction and its consequences on brain and behavior likely depend on the interaction of genes and environment, during development and at the time of drug exposure. Animal models are needed to analyze these variables and discover the neural mechanisms of addiction. This application consists of four highly integrated projects that revolve around the central hypothesis that mechanisms of neural plasticity are key determinants of all phases of addiction--the initial susceptibility to drug-taking, its maintenance and the long-term consequences that lead to craving and relapse. Project 1 uses two lines of rats selectively bred for the novelty-seeking trait (HR vs. LR) that predicts susceptibility to drug-taking. These rats will be exposed to cocaine, followed by various periods of abstinence, and tested with or without a social stressor. Cocaine's broad impact on neural remodeling will be indexed by assessing expression of a panel of neuroplasticity genes in relevant brain circuits, and measuring hippocampal neurogenesis. Selected target genes will be further characterized. Project 2 studies the neural impact of cocaine exposure in HR-bred and LR-bred rats and asks whether prior exposure to the drug occludes the ability of the individual to profit from subsequent positive experience (enriched environment). This will be indexed by dendritic morphology, neurogenesis and gene expression. Project 3 asks whether a manipulation that enhances hippocampal neurogenesis can protect against susceptibility to cocaine under control and stressful conditions, and whether this protective effect may be different in animals with different genetic backgrounds. Project 4 asks whether increased expression of a stress-related gene, the glucocorticoid receptor (GR) increases susceptibility to cocaine. It uses two related mouse transgenic models -a constitutive GR overexpressor and an inducible GR overexpressor to determine critical periods in development with the greatest impact on drug susceptibility. This work will provide a better molecular understanding of addiction-induced brain remodeling in individuals with different propensities for drug abuse. This should lead to novel, better-tailored drug targets for treating the early impact of addictive drugs or reversing their persistent effects that can trigger relapse. PROGRAM CHARACTERISTICS